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The role of immune cells and mediators in preeclampsia.

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  • 1. Department of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS, USA.
      Authors
    • Deer E 1
    • Herrock O 1
    • Campbell N 1
    • Fitzgerald S 1
    • Amaral LM 1
    • LaMarca B 1
    (6 authors)
  • 2. Emergency Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
      Authors
    • Cornelius D 2
    (1 author)

ORCIDs linked to this article

Nature reviews. Nephrology, 12 Jan 2023, 19(4):257-270
https://doi.org/10.1038/s41581-022-00670-0 PMID: 36635411 PMCID: PMC10038936

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Abstract 

Preeclampsia is a hypertensive disorder of major concern in pregnancy than can lead to intrauterine growth restriction, placental abruption and stillbirth. The pathophysiology of preeclampsia is multifactorial, including not only kidney dysfunction but also endothelial dysfunction, as the maternal endothelium becomes exposed to placental factors that are released into the circulation and increase systemic levels of vasoconstrictors, oxidative stress, anti-angiogenic factors and inflammatory mediators. Importantly, inflammation can lead to insufficient placental perfusion and low birthweight in offspring. Various innate and adaptive immune cells and mediators have been implicated in the development of preeclampsia, in which oxidative stress is associated with activation of the maternal inflammatory response. Immune cells such as regulatory T cells, macrophages, natural killer cells, and neutrophils are known to have major causative roles in the pathology of preeclampsia, but the contributions of additional immune cells such as B cells, inflammatory cytokines and anti-angiotensin II type 1 receptor autoantibodies are also now recognized. Immunological interventions, therefore, have therapeutic potential in this disease. Here, we provide an overview of the immune responses that are involved in the pathogenesis of preeclampsia, including the role of innate and adaptive immune cells and mediators.

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PMID: 36635411

The role of immune cells and mediators in preeclampsia

Evangeline Deer,1 Owen Herrock,1 Nathan Campbell,1 Denise Cornelius,2 Sarah Fitzgerald,1 Lorena M. Amaral,1 and Babbette LaMarca1,3,[env]
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Abstract

Preeclampsia is a hypertensive disorder of major concern in pregnancy than can lead to intrauterine growth restriction, placental abruption and stillbirth. The pathophysiology of preeclampsia is multifactorial, including not only kidney dysfunction but also endothelial dysfunction, as the maternal endothelium becomes exposed to placental factors that are released into the circulation and increase systemic levels of vasoconstrictors, oxidative stress, anti-angiogenic factors and inflammatory mediators. Importantly, inflammation can lead to insufficient placental perfusion and low birthweight in offspring. Various innate and adaptive immune cells and mediators have been implicated in the development of preeclampsia, in which oxidative stress is associated with activation of the maternal inflammatory response. Immune cells such as regulatory T cells, macrophages, natural killer cells, and neutrophils are known to have major causative roles in the pathology of preeclampsia, but the contributions of additional immune cells such as B cells, inflammatory cytokines and anti-angiotensin II type 1 receptor autoantibodies are also now recognized. Immunological interventions, therefore, have therapeutic potential in this disease. Here, we provide an overview of the immune responses that are involved in the pathogenesis of preeclampsia, including the role of innate and adaptive immune cells and mediators.

Introduction

Hypertensive disorders of pregnancy — a broad group that includes pre-existing hypertension, preeclampsia, gestational hypertension and eclampsia — complicate ~10% of pregnancies and are a major contributor to maternal mortality and morbidity1. Furthermore, the incidence of hypertensive disorders of pregnancy has increased from 16.3 million in 1990 to 18.08 million in 2019 worldwide2. In all types of hypertensive disorder of pregnancy, hypertension (defined as a blood pressure (BP) >140 mm Hg systolic or >90 mm Hg diastolic) is detected during pregnancy. Pre-existing or chronic hypertension complicates 5% of all pregnancies and comprises cases in which hypertension is identified before conception or at <20 weeksʼ gestation and persists for 12 weeks postpartum. Gestational hypertension occurs in ~6% of pregnancies and is diagnosed in women who develop hypertension before 20 weeks of gestation in the absence of proteinuria; BP typically returns to normotensive levels postpartum3,4. However, gestational hypertension is defined as preeclampsia if BP remains ≥140 mmHg after 20 weeks of gestation and one or more of the following are present — proteinuria, maternal organ dysfunction (including kidney, liver or brain dysfunction), abnormal Doppler sonography, or potential fetal growth restriction1. Preeclampsia affects 5% of pregnancies worldwide and is associated with worse patient outcomes, including kidney or liver damage, than gestational hypertension5–7. Preeclampsia can be classified as early-onset preeclampsia or late-onset preeclampsia, depending on whether if develops before or at 34 weeks of gestation8. Although the presenting features of the two conditions are similar, they have different maternal and fetal outcomes, heritability, biochemical marker and clinical features. Another difference between the two is that early-onset preeclampsia is complicated by uterine growth restriction whereas late-onset is not9. Eclampsia is a severe life-threatening complication of pregnancy that develops in 0.8% of pregnant women diagnosed with high BP and that causes seizures during and after delivery10,11. Haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome is a severe complication of preeclampsia or eclampsia that causes haemolysis, liver dysfunction and thrombocytopenia4,10; its incidence is 0.1–0.6% for all pregnancies and 4–12% in patients with preeclampsia12,13.

The causes of gestational hypertension, preeclampsia, eclampsia or HELLP syndrome remain unknown, but some underlying conditions such as pre-existing hypertension, kidney disease, and diabetes increase the risk of developing preeclampsia or gestational hypertension14. Key mechanisms underlying the development of hypertensive disorders of pregnancy include endothelial dysfunction, angiogenesis, impaired spiral uterine artery remodelling and inadequate trophoblast invasion15–17. Notably, immune dysregulation and inflammation are important contributors to the placental and kidney dysfunction that culminate in maternal hypertension17,18 (Fig. 1).

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Pathophysiology of hypertensive disorders during pregnancy.

Hypertensive disorders of pregnancy include gestational hypertension, preeclampsia, haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome and eclampsia, which complicate up to 10% of pregnancies and represent a substantial cause of maternal and fetal morbidity and mortality. Genetic susceptibility, environmental or maternal characteristics, and loss of immune tolerance can all contribute to inadequate placentation and can compromise the maternal–fetal interface. Poor placental perfusion causes tissue damage owing to ischaemia and hypoxia, and can impair fetal growth. These effects trigger the release of placental factors that promote widespread immune activation and organ dysfunction.

In this Review, we outline key immune mechanisms involved in the pathogenesis of preeclampsia, including the role of immune cells and mediators, and examine how these mechanisms contribute to the oxidative stress, endothelial dysfunction and hypertension that characterize this pregnancy disorder. Moreover, we consider the current management of preeclampsia and potential therapeutic strategies for its treatment.

Pathological alterations in preeclampsia

Placentation and formation of the maternal–fetal interface is a complex process that involves careful orchestration by trophoblasts and immune cells. For example, fetal trophoblast invasion of the maternal endometrium is essential to establish the maternal–fetal blood supply in pregnancy19. These trophoblasts promote the remodelling of maternal spiral arteries into low-resistance vessels throughout the pregnancy by replacing the endothelial cells of the spiral arteries20; smooth muscle cells and their respective autonomic innervation are also lost, which further reduces vascular resistance21. In preeclampsia, the invasion of extravillous trophoblasts into the myometrium is insufficient22, which leads to the formation of smaller, higher resistance vessels compared with a healthy pregnancy21. Moreover, the spiral arteries in preeclampsia fail to maintain adequate perfusion to support the growing fetus, which leads to progressive placental damage owing to ischaemia and hypoxia. The hypoxic placenta releases vasoactive factors such as tumour necrosis factor (TNF), soluble fms-like tyrosine kinase-1 (sFLT-1; also termed vascular endothelial receptor (VEGFR1)), and soluble endoglin (Fig. 2). These factors promote endothelial dysfunction and increased vascular resistance23,24.

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Mechanisms of endothelial dysfunction in preeclampsia.

Abnormal placentation triggers a cascade of events that activates the release of circulating factors, such as cytokines (for example, tumour necrosis factor (TNF) and IL-6), soluble fms-like tyrosine kinase 1 (sFlt-1) and angiotensin II type 1 receptor (AT1) autoantibodies that promote inflammation, create an angiogenic imbalance and induce oxidative stress. Collectively, these alterations result in endothelial dysfunction and hypertension, as well as kidney dysfunction during pregnancy. NF-κB, nuclear factor-κB; PIGF, placental growth factor; ROS, reactive oxygen species; sEng, soluble endoglin; VEGF, vascular endothelial growth factor.

Moreover, preeclampsia is associated with the pathological release of free radicals by the placenta. In a healthy pregnancy, the maternal and fetal oxygen demand increases oxygen metabolism at the mitochondrial level, which generates free radicals, including superoxide ions. Importantly, reactive oxygen species (ROS) control energy metabolism, cell proliferation and apoptosis, intracellular and intercellular signalling pathways, and biochemical reactions through oxidative–reductive processes25. Accordingly, placental ROS are present throughout a healthy pregnancy and are necessary for the cellular replication, proliferation and maturation processes that support embryo development and pregnancy maintenance26. However, in preeclampsia, impaired uteroplacental blood flow creates an imbalance between the production of ROS and antioxidants, which leads to oxidative stress, inflammation and apoptosis of syncytiotrophoblasts27 (Fig. 3). This oxidative stress also affects vascular responses, causing inadequate vascular remodelling, smooth muscle hypertrophy and cellular apoptosis26. Of note, we have previously shown that lower than normal mitochondrial oxidative stress is also associated with preeclampsia28.

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Mitochondrial dysfunction and the pathogenesis of preeclampsia.

Immune alterations characteristic of preeclampsia, such as the production of angiotensin II type 1 receptor autoantibodies (AT1-AAs), increased secretion of pro-inflammatory cytokines (including IL-6, IL-17 and tumour necrosis factor (TNF)) and enhanced natural killer (NK) cell cytolytic activity, induce cellular stress and mitochondrial DNA damage in the placenta. Accumulation of mitochondrial reactive oxygen species (mtROS) leads to DNA damage and affects ATP production, for example, through impairment in the electron transport chain (ETC). ROS and the pro-inflammatory mediators that are produced during this process contribute to the systemic inflammation observed during preeclampsia. JAK, Janus kinase.

In a healthy pregnancy, the immune response is balanced to achieve successful implantation while protecting the fetus from immune insults29. Chronic immune activation of CD4+ T cells, B cells, natural killer (NK) cells and macrophages, as well as activation of inflammatory pathways that involve the complement system and agonistic anti-angiotensin II type 1 receptor autoantibodies (AT1-AAs) are associated with placental ischaemia and have been implicated in the pathogenesis of preeclampsia. These immune factors are thought to sensitize women with preeclampsia to vasoconstrictors, such as angiotensin II30 (Box 1). The immune cell profile in pregnancy is dynamic but early spiral artery remodelling, for example, relies on an anti-inflammatory environment to ensure maternal–fetal tolerance. However, in contrast to normal pregnancy, pro-inflammatory cytokines such as TNF, IL-6 and IL-17 are elevated during preeclampsia31–34 and promote cytotoxic inflammatory responses35–37. For example, in decidual tissue from chorionic villus sampling, women who later developed preeclampsia had high levels of IL6 mRNA38. TNF and IL-6 have been implicated in endothelial dysfunction through decreased nitric oxide (NO) production and increased endothelin-1 production35,39,40, and can also modulate vascular resistance by increasing the production of anti-angiogenic factors41 such as sFlt-1. (Fig. 2) Chronic infusion of TNF or IL-6 into normal pregnant rats significantly increased BP, impaired renal haemodynamics and stimulated the production of AT1-AAs. Of note, chronic infusion of these pro-inflammatory cytokines did not have similar effects in non-pregnant rats42. In the pregnant rat, TNF infusion administered late in pregnancy increased BP and plasma markers of preeclampsia, such as sFlt-1, soluble endoglin, endothelin-1 and AT1AA35,43–45. TNF blockade with etanercept, which acts as a soluble TNF receptor, reduced BP and improved inflammation induced by placental ischaemia in the reduced uteroplacental perfusion pressure (RUPP) rat model of preeclampsia. Moreover, etanercept also lowered endothelin-1 expression in human umbilical vein endothelial cells in vitro following exposure to sera from RUPP-induced preeclampsia44,46. Similarly, administration of IL-17 in normal pregnant rats increased BP and caused placental oxidative stress through increases in mitochondrial ROS and AT1-AAs47 (Box 1). Another study showed that human umbilical vein endothelial cells supplemented with serum from women with preeclampsia had higher levels of endothelial cell respiration and mitochondrial ROS than those exposed to control serum7.

Box 1

AT1-AAs in preeclampsia

Healthy pregnancies are associated with increased activation of the renin–angiotensin–aldosterone system, combined with reduced responsiveness to the vasoconstrictive effects of angiotensin II (Ang II)192. Although levels of AngII are lower in women with preeclampsia than in women with healthy pregnancies, their sensitivity to AngII is enhanced192,193 and this effect is probably due to the presence of anti-Ang II type 1 receptor autoantibodies (AT1-AAs) in patients with preeclampsia152.

AT1-AAs activate the AT1 receptor by binding to a specific sequence on its second extracellular loop. This binding seems to enhance, rather than compete with, Ang II binding and its downstream signalling cascade, suggesting that AT1-AAs are allosteric AT1 ligands166,170,194,195 (Fig. 3). From a therapeutic perspective, small molecules that can bind this allosteric site might be able to block the effects of AT1-AAs or attenuate the effects of Ang II binding196.

Infusing AT1-AAs into pregnant rats and mice induces a preeclamptic phenotype197–199. Furthermore, in rats, AT1-AA treatment increased mRNA levels of preproendothelin (PPET-1), which is a precursor of vasoconstrictive endothelin-1, in the placenta and kidneys171. AT1-AAs might also contribute to the rise in soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin levels observed in patients with preeclampsia compared with those observed in healthy pregnancies167,200. For example, AngII or IgG isolated from patients with preeclampsia stimulate sFlt-1 production in human trophoblast cells, placental explants and pregnant mice201,202. Soluble endoglin is also elevated in pregnant mice or rats infused with AT1-AAs200,203. Additionally, AT1-AAs have been implicated in the preeclampsia-associated increases in reactive oxygen species levels in the placenta, kidney and endothelial progenitor cells198,204–206.

AT1-AA inhibition with n7AAc not only attenuated hypertension in the reduced uteroplacental perfusion pressure (RUPP) rat model but also improved placental and kidney respiration compared with controls172. Moreover, human umbilical vein endothelial cells exposed to sera from RUPP rats treated with n7AAc produced less mitochondrial reactive oxygen species (ROS) than cells exposed to sera from untreated animals207.

Notably, AT1-AA infusion decreases glomerular filtration rate, either through an increase in renal vascular resistance or through a decrease in renal blood flow in pregnant rats; combined infusion of AT1-AAs and Ang II enhanced these deleterious effects170,194. For example, AT1-AA infusion in pregnant rats reduced the vasodilatory response of kidney vessels to acetylcholine208.

The maternal vascular endothelium is an important target of preeclampsia-inducing factors, and severe endothelial dysfunction is not only associated with recurrent preeclampsia48 but also with maternal cardiovascular disease, and poor cardiometabolic and cerebral health in both the mother and the fetus27. The primary physiological function of endothelial cells is to maintain vascular function in response to changes in blood composition and provide a physical barrier that regulates the movement of proteins, water, ions and cells from the blood into the vessel wall48. Compared with healthy pregnancy, women with preeclampsia have significantly lower flow-mediated dilation, which is associated with an increase in endothelial damage27. The production and response to vasodilators is also altered in preeclampsia. For example, imaging of umbilical vein endothelium revealed that tissue from patients with preeclampsia failed to respond to ATP with appropriate Ca2+ bursts, which was associated with reduced NO production compared with that observed in tissue from healthy pregnancies49.

Circulating factors, such as sFlt-1 and VEGF contribute to the endothelial dysfunction that is triggered by excessive ROS and oxidative stress in preeclampsia (Fig. 2). VEGF is important for the growth of new blood vessels and the maintenance of endothelial cell health. In a healthy pregnancy, sFlt-1, which acts as a VEGF inhibitor, regulates angiogenesis and vasculogenesis26. However, in hypoxic conditions, Flt-1 cleavage increases and the rise in sFlt-1 levels promotes endothelial dysfunction26. Women with preeclampsia have increased levels of sFlt-1 compared with normotensive pregnant women50. Collectively, the milieu of anti-angiogenic factors, endothelial dysfunction, oxidative stress and chronic inflammation result in the cardiovascular dysfunction and hypertension seen in preeclampsia.

Innate immune system in preeclampsia

The innate immune system — including complement, macrophages, neutrophils and NK cells — not only protects the mother and fetus from infection but also contributes to the establishment of the maternal–fetal interface (Fig. 4). For example, macrophages and uterine NK (uNK) cells help to establish implantation and remodel uterine spiral arteries51,52. Innate immune cells also remove apoptotic cells in the uterus in combination with natural antibodies from innate-like B1 cells53.

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Immune alterations in preeclampsia.

The innate immune system is crucial to the formation of fetal vessels in healthy pregnancy, but can also contribute to inflammation and cell death in preeclampsia. a, Macrophages clear cellular debris in the remodelling uterus while also producing proteases to help to establish the fetal blood supply. b, The role of neutrophils in healthy pregnancy has not been fully elucidated but these cells can also clear cellular debris. c, Uterine natural killer (uNK) cells are very active in healthy pregnancies as they produce vascular endothelial growth factor (VEGF) and proteases that promote spiral artery remodelling; these cells also promote cell turnover in the rapidly changing uterus. d, Complement proteins are present in the uterine environment and seem to also contribute to cell turnover. C1q deficiency is associated with decreased fetal viability and improper placentation191, suggesting that complement is integral to placentation. e, B1 B cells spontaneously produce natural antibodies that contribute to maternal immunity and B2 B cells secrete asymmetric antibodies that shield fetal antigens from maternal killer cells. f, In preeclampsia, B cells produce anti-angiotensin II type 1 receptor autoantibodies (AT1-AAs), which contribute to immune activation and AT1 receptor activation, resulting in cardiovascular dysfunction. g, NK cells become activated through activating signals downstream of CD16 bound by antibodies in preeclampsia and contribute to cellular death. NK cells are also activated by cytokines that promote a cytolytic phenotype. h, Cytolytic NK cells can produce anti-angiogenic factors and inhibit vascularization of the placenta, therefore contributing to preeclampsia. i, Neutrophils produce more neutrophil extracellular traps (NETs) in preeclampsia than in healthy pregnancy. NETs can contribute to vascular fibrosis and cell death in the placenta. j, The abundance of pro-inflammatory macrophages, which produce tumour necrosis factor (TNF) and IL-6, increases in preeclampsia at stages in which anti-inflammatory macrophages would be dominant in a healthy pregnancy. k, Complement activation is also observed in the placentas of women with preeclampsia, where it promotes immune cell recruitment and tissue damage.

Macrophages

In pregnancy, decidual macrophages contribute to spiral artery remodelling by producing angiogenic factors54. In a healthy pregnancy, macrophages comprise ~20–30% of decidual leukocytes. Pro-inflammatory macrophages (also termed M1 macrophages) predominate in the first trimester (<12 weeksʼ gestation) and contribute to embryo implantation, placental formation and embryo development. However, the macrophage population comprises both pro- and anti-inflammatory macrophages (also termed M2 macrophages) during placental formation and trophoblast invasion of the endometrium. After the placenta has fully developed in the second trimester, anti-inflammatory macrophages predominate until labour, at which point pro-inflammatory macrophages become dominant again55. In contrast to a healthy pregnancy, preeclampsia is associated with a sustained increase in the M1-to-M2 ratio. Moreover, the number of Hofbauer cells, which are placental macrophages of fetal origin, as well as their expression of anti-inflammatory IL-10, are reduced in preeclampsia56.

In a healthy pregnancy, polarization of macrophages towards an anti-inflammatory phenotype is essential for maintenance of the pregnancy after successful implantation. Accordingly, dysregulated macrophage polarization is associated with inadequate uterine remodelling and deficient trophoblast invasion, which can lead to spontaneous abortion, preterm birth, and preeclampsia55. Specifically, M1 macrophages are more abundant in the placenta, decidua and surrounding uterine spiral arteries of women with preeclampsia than in tissues from healthy pregnancies57,58. Although the production of pro-inflammatory cytokines (for example, IL-6, TNF and IL-1β) by decidual macrophages has been implicated in recurrent spontaneous abortion59, the consequences of increased numbers of pro-inflammatory macrophages in preeclampsia have yet not been fully investigated. In addition, immunohistochemistry studies showed lower trophoblast invasion and higher macrophage infiltration in preeclamptic placentas compared with normal placentas in the third trimester57. In vitro studies demonstrated that macrophage secretion of TNF induced apoptosis in trophoblast cells, which might underlie the reduced trophoblast invasion and inadequate spiral artery remodelling observed in preeclampsia60.

Neutrophils

Neutrophils are present in the decidua from the first trimester and increase by 55% throughout a healthy pregnancy in humans61,62. However, circulating neutrophil counts are higher in patients with severe preeclampsia than in women with mild preeclampsia or normotensive women63. In preeclampsia, the release of placental micro-debris via syncytiotrophoblasts contributes to the inflammatory response and neutrophil extracellular traps (NETs) have been implicated in this process64. For example, exposure of circulating neutrophils to IL-8 or syncytiotrophoblast microparticles triggered their activation and release of NETs. Moreover, NETs are abundant in the intervillous space of preeclamptic placentae65. Compared with normotensive women, levels of plasma neutrophil elastase, which are indicative of neutrophil degranulation, are elevated in women with preeclampsia (matched for gestational age), especially in those with early-onset preeclampsia66. In addition to exposure to syncytiotrophoblast microparticles, up-regulation of cellular adhesion molecules on the endothelial surface, hyperlipidaemia-induced endothelial cell activation and TNF production have all been implicated as factors that can trigger neutrophil activation in preeclampsia67,68. Of note, although neutrophil counts seem to associate positively with the severity of preeclampsia, whether neutrophil activation is the cause or consequence of endothelial damage remains unclear.

Importantly, neutrophils also have a regulatory role in normal placental development and fetal tolerance. IL-8, which is a chemokine produced by neutrophils and other immune, epithelial and endothelial cells, contributes to placental development as it is involved in the regulation of angiogenesis, endothelial activation and cell migration or invasion69. However, IL-8 also mediates neutrophil transmigration and is associated with endothelial dysfunction, and can therefore contribute to the pathogenesis of preeclampsia by promoting neutrophil extravasation into the vascular wall of tissues and the release of oxidative stress molecules.

Neutrophils also have immunoregulatory functions that affect the production of pro- and anti-inflammatory cytokines, as well as the recruitment and polarization of T cells. For example, neutrophils can inhibit T cell proliferation and activation via their production of ROS and arginase 1 (ARG-1)61. Granulocytic myeloid derived suppressor cells can also exert an immunosuppressive effect via ARG-1. Of note, although pregnancy typically induces an increase in the frequency of these regulatory cells, this effect was not observed in women with preeclampsia, who also had lower serum levels of ARG-1 than women with a healthy pregnancy70.

NK cells

NK cells are granular, innate lymphocytes that represent 5–20% of all circulating lymphocytes71. NK cell function is determined by a balance between the signals received through their killer activating receptors (KARs) and killer inhibitory receptors (KIRs); additional signals received through cytokine receptors and CD16 further regulate NK cell activation72. Following activation, NK cells degranulate and release lysosomes that contain perforin and granzymes, which induce target cell lysis. Additionally, NK cells produce pro-inflammatory cytokines such as IFNγ and TNF, which promote the activation of neighbouring immune cells.

NK cells are the most abundant type of leukocyte in the decidua73. Most human peripheral blood NK cells are CD16+CD56dim whereas uNK cells are predominantly CD16CD56bright74. These CD16CD56bright uNK cells have a crucial role in trophoblast invasion and spiral artery remodelling through the production of cytokines such as IL-8 and CXC-chemokine ligand 10 (CXCL10; also known as IP10) and angiogenic factors such as VEGF and placental growth factor (PIGF)75,76. Of note, compared with NK cells from women with normal remodelling, NK cells from women with impaired spiral artery remodelling had an altered soluble mediator profile, which led to a failure to induce trophoblast chemotaxis and outgrowth in vitro77,78. Animal studies support the paradigm that uNK cells regulate trophoblast invasion and spiral artery remodelling79. In mice, uNK cell deficiency80,81 or impaired uNK cell expansion82 compromised spiral artery remodelling during pregnancy. Similarly, global NK cell deficiency in pregnant rats delayed spiral artery remodelling and reduced trophoblast invasion83. Moreover, in contrast to the regulatory and angiogenic factors released by NK cells in a normal pregnancy, in preeclamptic pregnancies, these cells secrete pro-inflammatory cytokines, such as TNF and IFNγ, which are elevated in circulation of preeclamptic pregnancies compared with healthy pregnancy, and might thus contribute to a loss of immunological tolerance84. High INF-γ levels can lead to fetal resorption, placental and trophoblast apoptosis and decreased VEGF secretion79,85,86.

uNK cells are characterized as non-cytolytic owing to differential expression of the inhibitory receptor, NKG2A. Co-engagement of NKG2A on uNK cells antagonizes their secretion of cytolytic granules87. uNK cells also recognize human leukocyte antigen (HLA)-C, which is the most polymorphic of the HLA antigens expressed by fetal trophoblasts; this interaction delivers inhibitory signals and promotes immune tolerance88. Interestingly, a specific KIR haplotype that can affect uNK cell binding to HLA-C expressed on invading trophoblast cells was associated with the risk of preeclampsia, intrauterine growth restriction, and recurring miscarriage89. Pregnant women with hypertension have increased numbers of circulating NK cells with enhanced cytolytic activity compared with normotensive pregnant women90–93. In rats, NK cells from placentas of preeclamptic animals also had a 5-fold increase in cytolytic activity compared with sham controls94. Moreover, we showed that rat uNK cells exposed to placental ischaemia cause hypertension, fetal growth restriction and an anti-angiogenic factor imbalance when transferred into normal pregnant rats95.

Complement system

The complement system is an integral component of the innate immunity and, although complement activation increases during normal pregnancy96, this activation is further enhanced in preeclampsia97. Complement can be activated through three pathways: the classical pathway, the lectin pathway, and the alternative pathway98. Alternative complement activation in early pregnancy is associated with an increased risk of developing preeclampsia99,100. In an animal model of placental ischaemia, inhibition of complement receptor 1 attenuated hypertension, further suggesting that the activation of the classical and alternative complement pathways might be involved in the pathogenesis of hypertension in preeclampsia101.

Complement activation leads to target opsonization through C3b, recruitment of pro-inflammatory cells through C3a and C5a, and formation of the membrane attack complex (MAC; also known as C5b–9). Soluble C5b–9 levels are significantly higher in women with hypertensive disorders of pregnancy, including preeclampsia, than in women with healthy pregnancies102. MAC insertion induces apoptosis in placental cytotrophoblasts, and potentially reduces the effectiveness of trophoblast invasion and spiral artery remodelling103. In animal models, inappropriate complement activation causes fetal loss through complement deposition and destruction of the fetoplacental unit104. C3a, C5a and MAC are also highly expressed in plasma during preeclampsia97,99,100,105–107 and patients who develop preeclampsia have high levels of complement factor B (CFB), CFH, and C1q early in pregnancy108. By contrast, plasma levels of several proteins involved in the lectin pathway, such as H-ficolin, M-ficolin and mannan-binding lectin serine protease 3 (MASP3) are lower in preeclamptic pregnancies than in healthy pregnancies, which suggests a link between dysfunction in the lectin pathway and preeclampsia109. Of note, polymorphisms that impair the synthesis of MASP1, which is involved in the lectin pathway, have been associated with an increased risk of preeclampsia110. Single-nucleotide polymorphisms in genes encoding complement proteins (C3), and complement regulatory proteins (CD46, CFI and CFH) have also been linked to preeclampsia111–113.

Adaptive immune system in preeclampsia

Adaptive immune responses driven by T and B cells can be directed against pathogens but also against allo- and autoantigens, and are characterized by the generation of immune memory that enhances the immune response to subsequent encounters with the same antigens. Of note, preeclampsia is more common in the first than in subsequent pregnancies and the use of barrier contraceptives that prevent exposure to sperm is associated with a higher risk of preeclampsia114,115. Similarly, the lack of prior contact with sperm or oocyte donor alloantigens in medically assisted reproduction increased the risk of preeclampsia compared with natural conception; repeated exposure to donor semen reduced the risk associated with sperm donation115,116. Collectively, these observations suggest that seminal fluid might induce adaptive immune tolerance to paternal antigens, thereby reducing the risk of preeclampsia. Accordingly, breakdown of tolerance to paternal antigens might result in inappropriate immune activation that leads to inflammation and promotes preeclampsia3.

Activated T cells can be polarized, depending on the cytokine milieu and activating signals, to adopt a pro-inflammatory (for example, T helper 1 (TH1) or TH17) or an anti-inflammatory (for example, T regulatory (Treg) or TH2) phenotype. TH1 cells and type 1 cytokines, such as IL-2, TNF and IFNγ, are central to cell-mediated immunity, whereas TH2 cells and type 2 cytokines, such as IL-4, IL-5, IL-6 and IL-13, have major roles in humoral immunity and control antibody production117. Imbalances between pro- and anti-inflammatory T cells seem to contribute to the pathogenesis of gestational hypertension and preeclampsia118 (Fig. 5). In a healthy pregnancy, progesterone production from the placenta promotes TH cell differentiation towards anti-inflammatory TH2 and Treg cell phenotypes, but in preeclampsia this differentiation is skewed towards pro-inflammatory TH1 and TH17 cell phenotypes119. This imbalance is also observed in other disorders of pregnancy, such as recurrent spontaneous abortion120. Furthermore, levels of the immunosuppressive cytokine IL-10, which contributes to fetal tolerance, are low in preeclampsia117,121.

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The roles of T and B cells in preeclampsia.

a, Antigen-presenting cells (APCs) activate and polarize CD4+ T helper (TH) cells. In preeclampsia, TH cells are polarized towards inflammatory TH1 or TH17 cell profiles. TH1 cells produce pro-inflammatory cytokines, such as IFN-γ and tumour necrosis factor (TNF), which are both increased in preeclampsia. TNF activates various immune cells and endothelial cells, whereas IFNγ is a potent activator of cytotoxic immune cells and promotes B cell activation. TH17 cells are important producers of pro-inflammatory IL-17, which is linked to immune dysregulation in multiple autoimmune disorders. b, B cells are divided into two main subsets: B1 B cells and B2 B cells. B1 cells are innate-like B cells that are associated with spontaneous activation and natural antibody production. B2 cells are classical B cells that require TH cell help to induce antigen-specific antibody production. c, The interaction between B2 B cells and TH cells involves co-stimulatory molecules such as CD40 and its ligand CD40L. T cell help enables B2 cell differentiation into plasma cells and long-lived memory B cells, which might contribute to long-term, anti-angiotensin II type 1 receptor autoantibodies (AT1-AAs) production postpartum. Similar to angiotensin II, AT1-AAs activate the AT1 receptor (AT1R), in addition to contributing to immune activation through antibody-dependent cellular cytotoxicity and, potentially, complement system activation. Moreover, T cell-derived pro-inflammatory cytokines not only induce activation of other pro-inflammatory leukocytes but also contribute to the oxidative stress and endothelial dysfunction that is observed in preeclampsia. Treg, regulatory T.

Regulatory T cells

Treg cells, which are characterized by the expression of CD4, CD25 and the transcription factor FOXP3, are key regulators of immune tolerance during pregnancy122. Treg cells regulate pro-inflammatory TH cells by suppressing their proliferation, for example, through the production of anti-inflammatory cytokines, by consuming IL-2 and by inhibiting antigen-presenting cell activity123, for example via cytotoxic T lymphocyte antigen 4. Interestingly, mismatching between maternal and fetal HLA-C is associated with polarization of CD4+ T cells to a Treg cell phenotype115,124. Furthermore, Treg cells can contribute to the maintenance of an anti-inflammatory microenvironment by modulating the activity of dendritic and NK cells125,126. Accordingly, Treg cells have a crucial role in maintaining an anti-inflammatory decidual milieu, and regulate implantation and placental development by controlling the decidual leukocyte network that facilitates cytotrophoblast development and trophoblast invasion126. In a healthy pregnancy, dendritic cells that phagocytose trophoblast debris secrete immunosuppressive cytokines such as IL-10 and transforming growth factor β (TGFβ), which promote Treg cell activity, help to regulate the numbers of NK cells and neutrophils, and inhibit the activation of pro-inflammatory TH cells117,125. By contrast, dendritic cell phagocytosis of necrotic trophoblasts, which are more abundant in preeclampsia owing to oxidative stress and/or hypoxic conditions, induces the release of pro-inflammatory cytokines such as TNF, IFNγ and IL-12.

Two studies reported that the frequency of circulating Treg cells was lower in preeclamptic pregnancies than in healthy pregnancies127 and the frequency of Treg cells in placental bed biopsy samples was also lower in preeclampsia than in healthy pregnancies128. Moreover, reduced expansion of Treg cells has been reported in preeclampsia and proposed to contribute to loss of tolerance to paternally derived fetal antigens129. Further insights were obtained using the rat RUPP model, which recapitulates some features of preeclampsia, including an increase in BP, enhanced inflammation (for example, high levels of TNF, IL-6, IL-17 and sFlt-1 in the circulation) and oxidative stress, and AT1-AA production coupled with reduced fetal and placental weight28,130,131. Importantly, adoptive transfer of Treg cells from rats with a normal pregnancy into RUPP rats reduced hypertension, suggesting that Treg cells have the capacity to attenuate preeclampsia132. Conversely, Treg cell depletion in early pregnancy under normal conditions increased uterine artery vascular resistance, indicating that these cells have a role in regulating uterine artery function133.

Helper T cells

Effector CD4+ T helper cells include TH1, TH2 and TH17 cells, which have distinct cytokine profiles and effector functions. RUPP rats have significantly higher circulating CD4+ T cell than controls134. The adoptive transfer of CD4+ T cells from female RUPP rats into healthy pregnant rats induces changes characteristic of preeclampsia, including an increase in BP and mitochondrial ROS (mtROS) levels134,135. Moreover, T cell-deficient nude rats develop preeclampsia-like symptoms following adoptive transfer of placental CD4+ T cells from women with preeclampsia131, which supports a role for T cell populations in the pathogenesis of preeclampsia. Our previous studies have shown that CD4+ T cells isolated from the placentas of patients with preeclampsia secrete TNF, IL-6, IL-17 and the anti-angiogenic factor sFlt-1, both in culture and following adoptive transfer into pregnant nude athymic rats131. Placental CD4+ T cells have also been implicated in the activation of B cells that secrete AT1-AA136 (Box 1) which contributes to increased circulating inflammatory cytokines, the antiangiogenic factor sFlt-1 and the vasoconstrictor endothelin 1 (ET-1)6,121,134,137.

In a healthy pregnancy, TH2 cells increase in the circulation, whereas they decrease in preeclamptic pregnancies125. This dysregulation is typically observed in the first month of preeclamptic pregnancies and is accompanied by an increase in the numbers of circulating and placental CD4+ TH1 cells, pro-inflammatory cytokine levels, autoantibody production and oxidative stress121.

CD4+ TH17 cells are pro-inflammatory and secrete IL-17, IL-23 and IL-22 (ref. 138). Although these cells are typically involved in the immune response to extracellular pathogen, they have also been implicated in the pathogenesis of many autoimmune diseases and inflammatory disorders139. Th1-type immunity in preeclampsia increases levels of cytokines such as IL-6 and IL-1β, which further promotes the differentiation of TH17 cells140,141. In preeclampsia, the numbers of circulating and placental TH17 cells increase compared with those observed in women with a healthy pregnancy. In the RUPP model, BP, inflammation, oxidative stress and AT1-AA production increases, whereas fetal and placental weight are lower than in normal controls. These effects in RUPP animals can be replicated in normal pregnant rats through the adoptive transfer of RUPP-induced TH17 cells142. IL-17 has been implicated in vascular dysfunction owing to its activation of Rho-kinase, which disrupts the production of endothelial nitric oxide synthase (eNOS) by phosphorylating the inhibitory site Thr495, and leads to an increase in vascular tone143,144. Moreover, eNOS inhibition increases leukocyte adhesion to the vasculature, which promotes vascular inflammation and hypertension145. Blockade of IL-17 signalling with an IL-17 receptor C antibody significantly decreased TH17 cell number, BP, ROS and AT1-AA production, as well as improving placenta and pup weight in the RUPP rat model146. Soluble endoglin acts as an inhibitor of TGFβ receptor signalling and therefore compromises Treg cell differentiation and FOXP3 expression141. Since FOXP3 induction restrains the differentiation of TH17 cells, higher expression of endoglin might promote an increase in TH17 cell populations in preeclampsia147.

B cells

During a normal pregnancy, B cells promote a fetus-tolerant immune environment. However, these lymphocytes can also produce antibodies against paternal antigens, as well as autoantibodies, which can lead to pregnancy complications. B cells comprise not only classical B2 B cells but also innate-like B1 B cells, which are associated with T cell-independent antibody responses and produce ‘natural’ low-specificity antibodies, which are typically of the IgM class and specific for lipid antigens148,149. B2 cells are derived from common lymphoid progenitor cells and represent the dominant, classical B cells that are associated with T cell-dependent antibody responses. By contrast, B1 cells develop from progenitor cells in the fetal liver and are only predominant in early life.

B1 cells can be categorized according to their expression of CD5. B1a cells are CD5+ and have been implicated in autoimmunity and autoantibody production in preeclampsia, whereas B1b cells are CD5− and are associated with the production of natural anti-pathogen antibodies150. B1a cell frequency in the placenta decreases as normal pregnancy progresses but is elevated in late preeclamptic pregnancy151. Moreover, one study reported that CD19+CD5+ B cells isolated from women with preeclampsia produced AT1-AA (Box 1) in vitro151. Several other autoantibodies have been detected in preeclampsia, including antibodies specific for the α1 adrenergic receptor, the anticoagulation proteins C and S, and thyroid antigens152–154, but these autoantibodies have not been specifically linked to B1 or B2 cells.

AT1-AAs (Box 1) have been identified in circulation up to 7 years postpartum in women with preeclamptic pregnancies155,156. This finding suggests the presence of long-lived memory B cells in preeclampsia, which implicates the involvement of T cell-dependent antibody responses and B2 cells. Of note, the frequency of Treg cells correlated negatively with the frequency of memory B cells in women with preeclampsia but not in those with a healthy pregnancy157. Interestingly, adoptive transfer of CD4+ T cells from the RUPP model of preeclampsia induces the secretion of AT1-AAs in pregnant control rats130 but blockade of CD40L on CD4+ T cells, which is a key mediator of T cell–B cell interactions, or B cell depletion, prevents the development of hypertension and AT1-AA production in this model158. Adoptive transfer of placental CD4+ T cells from women with preeclampsia women into nude athymic pregnant rats also results in hypertension and AT1-AA formation, which are associated with inflammatory cytokine production and low birthweight136.

Therapeutic strategies for preeclampsia

Traditional screening approaches to identify women at risk of preeclampsia rely on the assessment of clinical risk factors such as age, BMI and underlying renal or cardiovascular disorders early in pregnancy. These risk factors are treated independently without an assessment of the level of risk, including the presence of additional factors that can increase the risk of developing preeclampsia. Although this approach is simple, the detection rates for preterm preeclampsia (~40%) and term preeclampsia (~35%) are low8. In addition to the traditional clinical parameters of high BP and increased uterine artery resistance, laboratory and ultrasound findings are used to predict early-onset preeclampsia and intrauterine growth restriction. Commonly used laboratory tests include the measurement of circulating markers of inflammation, angiogenesis, lipid metabolism, coagulation, fetoplacental endocrine function, cardiac function, kidney function and oxidative stress. These markers, coupled with the aforementioned clinical risk factors, BP, PlGF levels and uterine artery resistance index are useful in diagnosing and assessing the risk of preeclampsia in women at 11–14 weeks of gestation8. Additional risk factors, such as obesity, can also be used to predict the risk of preeclampsia8. Of note, obesity has been implicated in late-onset preeclampsia159 and reducing gestational weight gain was associated with a lower risk of developing preeclampsia160.

Currently, delivery of the fetal–placental unit is the only available intervention in cases of preeclampsia. Angiotensin receptor blockers, although useful to decrease BP, improve kidney function and decrease levels of anti-angiogenic factors161–163, are contraindicated in pregnancy owing to their teratogenic effects164. An alternative strategy for treating preeclampsia might be to target AT1-AAs. A seven amino acid sequence peptide (7AA) that binds to AT1-AAs and prevents them from binding to the AT1 receptor165,166 improved growth restriction, placental apoptosis, calcium mobilization, proteinuria, hypertension, NO bio-availability, NK cell activation, placental mitochondrial respiration, renal mitochondrial respiration, mtROS and cerebrovascular function in the RUPP rat model of preeclampsia and in an AT1-AA-induced rat model of preeclampsia; positive results were also obtained in cell culture studies167–173.

Rituximab, which is used to treat autoimmune disorders and B cell cancers, represents another approach to targeting AT1-AA in preeclampsia174–176. In a rat model of preeclampsia, rituximab decreased total B cell numbers, and circulating levels of AT1-AAs and TNF, tissue ET-1 levels and maternal BP177. However, despite the beneficial effects of rituximab in animal models, maternal B cell depletion probably poses risks to the mother and the fetus. Currently, there are no indications that rituximab exposure during pregnancy increases fetal malformations or other adverse events beyond those reported in other conditions treated with rituximab178–180. For example, loss of maternal antibodies and exposure to rituximab in fetal life increases the risk of infection in the mother and neonate. In one reported case of neonatal exposure to rituximab, the child had no B cells at birth but cell numbers had normalized by 4 months of age and the child was able to receive standard vaccinations181.

Targeting complement might be beneficial in some women with severe preeclampsia or HELLP syndrome, in whom alternative complement activation is enhanced182. Supplementing sera collected from these patients with the complement inhibitor eculizumab reduced complement-mediated killing of target cells182. Moreover, a patient with severe preeclampsia and HELLP syndrome who developed atypical haemolytic uraemic syndrome (aHUS) requiring kidney replacement therapy responded to treatment with eculizumab183–185. Of note, in a study of two mothers treated with eculizumab during pregnancy, levels of eculizumab–C5 complexes were minimal in fetal plasma and complement activation was unaffected in the newborns184. Urinary C5b-9 levels might help to identify patients with severe preeclampsia and enhanced complement activation185.

Additionally, anti-inflammatory therapeutics might be effective in preeclampsia. For example, statins might correct pathophysiological pathways underlying the development of preeclampsia and reduce inflammation186. In particular, pravastatin has been used in preclinical studies and in the clinical setting to reverse the pregnancy-specific angiogenic imbalance, restore endothelial health, and prevent oxidative and inflammatory injury186,187. Furthermore, treatment with a low dose of aspirin in women at a high risk of preterm preeclampsia lowered the incidence of preeclampsia up to 36 weeksʼ gestation188, potentially owing to its anti-inflammatory effects.

Immunomodulatory therapies targeting CD4+ T cells and NK cells, such as NK cell depletion and inhibition of T cell activation have been investigated in rat models of preeclampsia and have the potential to decrease the production of pro-inflammatory mediators such as TNF and cytolytic NK cell activity, while stimulating TH2 cell differentiation. Of note, 17-orthohydroxyprogesteron caproate (17-OHPC), which is effective in preventing preterm labour189 also lowered hypertension, pro-inflammatory immune cell numbers and cytokine levels in the RUPP rat model of preeclampsia compared with controls190.

Conclusion

Immune cells are crucial to successful implantation and establishment of the maternal–fetal interface. However, immune dysregulation and inflammation have also been implicated in preeclampsia. Several types of immune cell are present in the decidua, including different T cell subsets, B cells, NK cells and macrophages. In healthy pregnancies, these cells are regulated to enable fetal tolerance but they can also become dysregulated and instead promote inflammation, oxidative stress and endothelial dysfunction, as observed in preeclampsia. Although the pathophysiology of preeclampsia is multifactorial, interventions that target the immune system have therapeutic potential. Understanding how the innate and adaptive immune systems work together to ensure fetal–maternal tolerance is therefore crucial to enable the development of new therapeutic approaches for hypertensive disorders of pregnancy.

​

Key points

  • Endothelial dysfunction, angiogenesis, spiral uterine artery remodelling and inadequate trophoblast invasion are key contributors to the genesis of hypertensive disorders during pregnancy.

  • An altered immune response might have a pivotal role in the development of preeclampsia, eclampsia and haemolysis, elevated liver enzymes and low platelets syndrome.

  • Insufficient or inadequate regulation of the immune system, activation of innate immune cells and imbalanced differentiation of T helper cell subsets create a cytotoxic environment that results in oxidative stress, endothelial dysfunction and intrauterine growth restriction.

  • T helper cells facilitate the activation of B cells that secrete anti-angiotensin II type 1 receptor autoantibodies, which can cause hypertension, cerebral dysfunction, kidney dysfunction and intrauterine growth restriction in response to placental ischaemia.

  • New therapeutics that target the pro-inflammatory response during preeclampsia have potential to attenuate the effects of the systemic factors that promote the development of this hypertensive disorder of pregnancy.

Glossary

Fetal resorptionThe disintegration and absorption of one or more fetuses in the uterus after the completion of organogenesis.
Flow-mediated dilationA vascular function test traditionally performed in the brachial artery, which measures the change in artery diameter in response to reactive hyperaemia.
Hofbauer cellsA diverse population of fetal macrophages that reside within placental tissue (in the chorionic villus); they are present as early as 18 days post-conception and persist throughout pregnancy.
Spiral uterine artery remodelingAn adaptive process in pregnancy that allows placental blood flow volume to increase while blood flow resistance decreases.
SyncytiotrophoblastsA specialized, continuous layer of epithelial cells that cover the surface of embryonic placental villi and are in direct contact with maternal blood.

Footnotes

Competing interests

The authors declare no competing interests.

References

1. Braunthal S & Brateanu A Hypertension in pregnancy: pathophysiology and treatment. SAGE Open Med. 7, 2050312119843700 (2019). [Europe PMC free article] [Abstract] [Google Scholar]
2. Wang W et al. Epidemiological trends of maternal hypertensive disorders of pregnancy at the global, regional, and national levels: a population-based study. BMC Pregnancy Childbirth 21, 1–10 (2021). [Europe PMC free article] [Abstract] [Google Scholar]
3. Aneman I et al. Mechanisms of key innate immune cells in early-and late-onset preeclampsia. Front. Immunol 11, 1864 (2020). [Europe PMC free article] [Abstract] [Google Scholar]
4. Shen M et al. Comparison of risk factors and outcomes of gestational hypertension and pre-eclampsia. PLoS One 12, e0175914 (2017). [Europe PMC free article] [Abstract] [Google Scholar]
5. Papageorghiou AT et al. Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study. Am. J. Obstet. Gynecol 225, 289.e1–289.e17 (2021). [Europe PMC free article] [Abstract] [Google Scholar]
6. Jena MK, Sharma NR, Petitt M, Maulik D & Nayak NR Pathogenesis of preeclampsia and therapeutic approaches targeting the placenta. Biomolecules 10, 953 (2020). [Europe PMC free article] [Abstract] [Google Scholar]
7. Deer E et al. Vascular endothelial mitochondrial oxidative stress in response to preeclampsia: a role for angiotensin II type 1 autoantibodies. Am. J. Obstet. Gynecol. MFM 3, 100275 (2021). [Europe PMC free article] [Abstract] [Google Scholar]
8. Magee LA et al. The 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis & management recommendations for international practice. Pregnancy Hypertens. 27, 148–169 (2022). [Abstract] [Google Scholar]
9. Redman C Early and late onset preeclampsia: two sides of the same coin. Pregnancy Hypertens. 7, 58 (2017). [Google Scholar]
10. Martin JN Jr & Morris RF in Sex Differences in Cardiovascular Physiology and Pathophysiology 121–136 (Elsevier, 2019). [Google Scholar]
11. Fishel Bartal M & Sibai BM Eclampsia in the 21st century. Am. J. Obstet. Gynecol 226, S1237–S1253 (2020). [Abstract] [Google Scholar]
12. Shahzad N, Irshad B, Sami N & Nadeem D Comparison of dexamethasone versus betamethasone for the management of females with HELLP syndrome. Pak. J. Med. Health Sci 11, 593–597 (2017). [Google Scholar]
13. Stojanovska V & Zenclussen AC Innate and adaptive immune responses in HELLP syndrome. Front. Immunol 11, 667 (2020). [Europe PMC free article] [Abstract] [Google Scholar]
14. Wisner K Gestational hypertension and preeclampsia. MCN Am. J. Matern. Child Nurs 44, 170 (2019). [Abstract] [Google Scholar]
15. Burke SD & Karumanchi SA Hypertension 62, 1013–1014 (2013). [Abstract] [Google Scholar]
16. Pratt A et al. Placenta-derived angiogenic proteins and their contribution to the pathogenesis of preeclampsia. Angiogenesis 18, 115–123 (2015). [Abstract] [Google Scholar]
17. Possomato-Vieira JS & Khalil RA Mechanisms of endothelial dysfunction in hypertensive pregnancy and preeclampsia. Adv. Pharmacol 77, 361–431 (2016). [Europe PMC free article] [Abstract] [Google Scholar]
18. Geldenhuys J, Rossouw TM, Lombaard HA, Ehlers MM & Kock MM Disruption in the regulation of immune responses in the placental subtype of preeclampsia. Front. Immunol 9, 1659 (2018). [Europe PMC free article] [Abstract] [Google Scholar]
19. Pijnenborg R, Vercruysse L & Hanssens M The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 27, 939–958 (2006). [Abstract] [Google Scholar]
20. Brosens I, Robertson WB & Dixon HG The physiological response of the vessels of the placental bed to normal pregnancy. J. Pathol. Bacteriol 93, 569–579 (1967). [Abstract] [Google Scholar]
21. Burton GJ, Woods AW, Jauniaux E & Kingdom JC Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta 30, 473–482 (2009). [Europe PMC free article] [Abstract] [Google Scholar]
22. Lyall F, Robson SC & Bulmer JN Spiral artery remodeling and trophoblast invasion in preeclampsia and fetal growth restriction: relationship to clinical outcome. Hypertension 62, 1046–1054 (2013). [Abstract] [Google Scholar]
23. Enkhmaa D et al. Preeclampsia and vascular function: a window to future cardiovascular disease risk. J. Women’s Health 25, 284–291 (2016). [Europe PMC free article] [Abstract] [Google Scholar]
24. Cerdeira AS, Agrawal S, Staff AC, Redman CW & Vatish M Angiogenic factors: potential to change clinical practice in pre-eclampsia? BJOG 125, 1389–1395 (2018). [Europe PMC free article] [Abstract] [Google Scholar]
25. Bizerea TO et al. The link between selenium, oxidative stress and pregnancy induced hypertensive disorders. Clin. Lab 64, 1593–1610 (2018). [Abstract] [Google Scholar]
26. Sánchez-Aranguren LC, Prada CE, Riaño-Medina CE & Lopez M Endothelial dysfunction and preeclampsia: role of oxidative stress. Front. Physiol 5, 372 (2014). [Europe PMC free article] [Abstract] [Google Scholar]
27. McElwain CJ, Tuboly E, McCarthy FP & McCarthy CM Mechanisms of endothelial dysfunction in pre-eclampsia and gestational diabetes mellitus: windows into future cardiometabolic health? Front. Endocrinol 11, 655 (2020). [Europe PMC free article] [Abstract] [Google Scholar]
28. Deer E et al. Vascular endothelial mitochondrial oxidative stress in response to preeclampsia: a role for AT1-AAs. Am. J. Obstet. Gynecol. MFM 3, 100275 (2021). [Europe PMC free article] [Abstract] [Google Scholar]
29. Mor G, Aldo P & Alvero AB The unique immunological and microbial aspects of pregnancy. Nat. Rev. Immunol 17, 469–482 (2017). [Abstract] [Google Scholar]
30. Gant NF, Daley GL, Chand S, Whalley PJ & MacDonald PC A study of angiotensin II pressor response throughout primigravid pregnancy. J. Clin. Invest 52, 2682–2689 (1973). [Europe PMC free article] [Abstract] [Google Scholar]
31. Madazli R, Aydin S, Uludag S, Vildan O & Tolun N Maternal plasma levels of cytokines in normal and preeclamptic pregnancies and their relationship with diastolic blood pressure and fibronectin levels. Acta Obstet. Gynecol. Scand 82, 797–802 (2003). [Abstract] [Google Scholar]
32. Szarka A, Rigó J, Lázár L, Bekő G & Molvarec A Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array. BMC Immunol. 11, 1–9 (2010). [Europe PMC free article] [Abstract] [Google Scholar]
33. Jonsson Y et al. Cytokine mapping of sera from women with preeclampsia and normal pregnancies. J. Reprod. Immunol 70, 83–91 (2006). [Abstract] [Google Scholar]
34. Aggarwal R et al. Association of pro- and anti-inflammatory cytokines in preeclampsia. J. Clin. Lab. Anal 33, e22834 (2019). [Europe PMC free article] [Abstract] [Google Scholar]
35. LaMarca BBD, Cockrell K, Sullivan E, Bennett W & Granger JP Role of endothelin in mediating tumor necrosis factor-induced hypertension in pregnant rats. Hypertension 46, 82–86 (2005). [Abstract] [Google Scholar]
36. Formby B Immunologic response in pregnancy: its role in endocrine disorders of pregnancy and influence on the course of maternal autoimmune diseases. Endocrinol. Metab. Clin. North. Am 24, 187–205 (1995). [Abstract] [Google Scholar]
37. Gadonski G et al. Hypertension produced by reductions in uterine perfusion in the pregnant rat: role of interleukin 6. Hypertension 48, 711–716 (2006). [Abstract] [Google Scholar]
38. Prins J et al. Altered expression of immune-associated genes in first-trimester human decidua of pregnancies later complicated with hypertension or foetal growth restriction. Placenta 33, 453–455 (2012). [Abstract] [Google Scholar]
39. Kharfi A et al. Trophoblastic remodeling in normal and preeclamptic pregnancies: implication of cytokines. Clin. Biochem 36, 323–331 (2003). [Abstract] [Google Scholar]
40. Yoshizumi M, Perrella MA, Burnett J Jr & Lee ME Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life. Circulation Res. 73, 205–209 (1993). [Abstract] [Google Scholar]
41. Maruotti N, Cantatore FP, Crivellato E, Vacca A & Ribatti D Angiogenesis in rheumatoid arthritis. Histol. Histopathol 21, 557–566 (2006). [Abstract] [Google Scholar]
42. LaMarca BD, Ryan MJ, Gilbert JS, Murphy SR & Granger JP Inflammatory cytokines in the pathophysiology of hypertension during preeclampsia. Curr. Hypertens. Rep 9, 480–485 (2007). [Abstract] [Google Scholar]
43. LaMarca B et al. Autoantibodies to the angiotensin type I receptor in response to placental ischemia and tumor necrosis factor α in pregnant rats. Hypertension 52, 1168–1172 (2008). [Europe PMC free article] [Abstract] [Google Scholar]
44. LaMarca B et al. Hypertension in response to chronic reductions in uterine perfusion in pregnant rats: effect of tumor necrosis factor-α blockade. Hypertension 52, 1161–1167 (2008). [Europe PMC free article] [Abstract] [Google Scholar]
45. Murphy SR, LaMarca BBD, Parrish M, Cockrell K & Granger JP Control of soluble fms-like tyrosine-1 (sFlt-1) production response to placental ischemia/hypoxia: role of tumor necrosis factor-α. Am. J. Physiol. Regul. Integr. Comp. Physiol 304, R130–R135 (2013). [Europe PMC free article] [Abstract] [Google Scholar]
46. Cunningham MW et al. Tumor necrosis factor alpha (TNF-α) blockade improves natural killer cell (NK) activation, hypertension, and mitochondrial oxidative stress in a preclinical rat model of preeclampsia. Hypertens. Pregnancy 39, 399–404 (2020). [Europe PMC free article] [Abstract] [Google Scholar]
47. Dhillion P et al. IL-17-mediated oxidative stress is an important stimulator of AT1-AA and hypertension during pregnancy. Am. J. Physiol. Regulatory Integr. Comp. Physiol 303, R353–R358 (2012). [Europe PMC free article] [Abstract] [Google Scholar]
48. Boeldt D & Bird I Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia. J. Endocrinol 232, R27 (2017). [Europe PMC free article] [Abstract] [Google Scholar]
49. Krupp J et al. The loss of sustained Ca2+ signaling underlies suppressed endothelial nitric oxide production in preeclamptic pregnancies: implications for new therapy. Am. J. Physiol. Heart Circulatory Physiol 305, H969–H979 (2013). [Europe PMC free article] [Abstract] [Google Scholar]
50. Maynard SE et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Invest 111, 649–658 (2003). [Europe PMC free article] [Abstract] [Google Scholar]
51. Vishnyakova P, Elchaninov A, Fatkhudinov T & Sukhikh G Role of the monocyte-macrophage system in normal pregnancy and preeclampsia. Int. J. Mol. Sci 20, 10.3390/ijms20153695 (2019). [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
52. Faas MM & de Vos P Uterine NK cells and macrophages in pregnancy. Placenta 56, 44–52 (2017). [Abstract] [Google Scholar]
53. Nguyen TG, Ward CM & Morris JM To B or not to B cells-mediate a healthy start to life. Clin. Exp. Immunol 171, 124–134 (2013). [Abstract] [Google Scholar]
54. Lash GE et al. Decidual macrophages: key regulators of vascular remodeling in human pregnancy. J. Leukoc. Biol 100, 315–325 (2016). [Abstract] [Google Scholar]
55. Yao Y, Xu XH & Jin L Macrophage polarization in physiological and pathological pregnancy. Front. Immunol 10, 792 (2019). [Europe PMC free article] [Abstract] [Google Scholar]
56. Reyes L & Golos TG Hofbauer cells: their role in healthy and complicated pregnancy. Front. Immunol 9, 2628 (2018). [Europe PMC free article] [Abstract] [Google Scholar]
57. Reister F et al. The distribution of macrophages in spiral arteries of the placental bed in pre-eclampsia differs from that in healthy patients. Placenta 20, 229–233 (1999). [Abstract] [Google Scholar]
58. Ma Y, Ye Y, Zhang J, Ruan CC & Gao PJ Immune imbalance is associated with the development of preeclampsia. Medicine 98, e15080 (2019). [Europe PMC free article] [Abstract] [Google Scholar]
59. Tsao FY, Wu MY, Chang YL, Wu CT & Ho HN M1 macrophages decrease in the deciduae from normal pregnancies but not from spontaneous abortions or unexplained recurrent spontaneous abortions. J. Formos. Med. Assoc 117, 204–211 (2018). [Abstract] [Google Scholar]
60. Reister F et al. Macrophage-induced apoptosis limits endovascular trophoblast invasion in the uterine wall of preeclamptic women. Lab. Invest 81, 1143–1152 (2001). [Abstract] [Google Scholar]
61. Bert S, Ward EJ & Nadkarni S Neutrophils in pregnancy: new insights into innate and adaptive immune regulation. Immunology 164, 665–676 (2021). [Europe PMC free article] [Abstract] [Google Scholar]
62. Dockree S, Shine B, Pavord S, Impey L & Vatish M White blood cells in pregnancy: reference intervals for before and after delivery. EBioMedicine 74, 103715 (2021). [Europe PMC free article] [Abstract] [Google Scholar]
63. Canzoneri BJ, Lewis DF, Groome L & Wang Y Increased neutrophil numbers account for leukocytosis in women with preeclampsia. Am. J. Perinatol 26, 729–732 (2009). [Europe PMC free article] [Abstract] [Google Scholar]
64. Giaglis S et al. Neutrophil migration into the placenta: good, bad or deadly? Cell Adhes. Migr 10, 208–225 (2016). [Europe PMC free article] [Abstract] [Google Scholar]
65. Gupta AK, Hasler P, Holzgreve W, Gebhardt S & Hahn S Induction of neutrophil extracellular DNA lattices by placental microparticles and IL-8 and their presence in preeclampsia. Hum. Immunol 66, 1146–1154 (2005). [Abstract] [Google Scholar]
66. Gupta AK, Gebhardt S, Hillermann R, Holzgreve W & Hahn S Analysis of plasma elastase levels in early and late onset preeclampsia. Arch. Gynecol. Obstet 273, 239–242 (2006). [Abstract] [Google Scholar]
67. Bajnok A, Ivanova M, Rigó J & Toldi G The distribution of activation markers and selectins on peripheral T lymphocytes in preeclampsia. Mediators Inflamm. 2017, 8045161 (2017). [Europe PMC free article] [Abstract] [Google Scholar]
68. Goksu Erol AY, Nazli M & Elis Yildiz S Significance of platelet endothelial cell adhesion molecule-1 (PECAM-1) and intercellular adhesion molecule-1 (ICAM-1) expressions in preeclamptic placentae. Endocrine 42, 125–131 (2012). [Abstract] [Google Scholar]
69. Yang W et al. miR-125b enhances IL-8 production in early-onset severe preeclampsia by targeting sphingosine-1-phosphate lyase 1. PLoS One 11, e0166940 (2016). [Europe PMC free article] [Abstract] [Google Scholar]
70. Wang Y et al. Inhibition of pregnancy-associated granulocytic myeloid-derived suppressor cell expansion and arginase-1 production in preeclampsia. J. Reprod. Immunol 127, 48–54 (2018). [Abstract] [Google Scholar]
71. Langers I, Renoux VM, Thiry M, Delvenne P & Jacobs N Natural killer cells: role in local tumor growth and metastasis. Biologics 6, 73–82 (2012). [Europe PMC free article] [Abstract] [Google Scholar]
72. Cornish EF, Filipovic I, Åsenius F, Williams DJ & McDonnell T Innate immune responses to acute viral infection during pregnancy. Front. Immunol 11, 572567 (2020). [Europe PMC free article] [Abstract] [Google Scholar]
73. Trundley A & Moffett A Human uterine leukocytes and pregnancy. Tissue Antigens 63, 1–12 (2004). [Abstract] [Google Scholar]
74. Nishikawa K et al. Accumulation of CD16−CD56+ natural killer cells with high affinity interleukin 2 receptors in human early pregnancy decidua. Int. Immunol 3, 743–750 (1991). [Abstract] [Google Scholar]
75. Kalkunte S et al. Evolution of non-cytotoxic uterine natural killer cells. Am. J. Reprod. Immunol 59, 425–432 (2008). [Europe PMC free article] [Abstract] [Google Scholar]
76. Hanna J et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat. Med 12, 1065–1074 (2006). [Abstract] [Google Scholar]
77. Fukui A et al. Uterine and circulating natural killer cells and their roles in women with recurrent pregnancy loss, implantation failure and preeclampsia. J. Reprod. Immunol 90, 105–110, (2011). [Abstract] [Google Scholar]
78. Wallace AE, Host AJ, Whitley GS & Cartwright JE Decidual natural killer cell interactions with trophoblasts are impaired in pregnancies at increased risk of preeclampsia. Am. J. Pathol 183, 1853–1861 (2013). [Europe PMC free article] [Abstract] [Google Scholar]
79. Liu Z, Chen Y, Yang Y & Peng J-P The effect on MHC class II expression and apoptosis in placenta by IFNγ administration. Contraception 65, 177–184 (2002). [Abstract] [Google Scholar]
80. Greenwood J et al. Ultrastructural studies of implantation sites from mice deficient in uterine natural killer cells. Placenta 21, 693–702 (2000). [Abstract] [Google Scholar]
81. Albrecht ED & Pepe GJ Regulation of uterine spiral artery remodeling: a review. Reprod. Sci 27, 1932–1942 (2020). [Europe PMC free article] [Abstract] [Google Scholar]
82. Sliz A et al. Gab3 is required for IL-2- and IL-15-induced NK cell expansion and limits trophoblast invasion during pregnancy. Sci. Immunol 4, eaav3866 (2019). [Europe PMC free article] [Abstract] [Google Scholar]
83. Chakraborty D, Rumi MK & Soares M NK cells, hypoxia and trophoblast cell differentiation. Cell Cycle 11, 2427–2430 (2012). [Europe PMC free article] [Abstract] [Google Scholar]
84. Raghupathy R Cytokines as key players in the pathophysiology of preeclampsia. Med. Princ. Pract 22, 8–19 (2013). [Europe PMC free article] [Abstract] [Google Scholar]
85. Liu HY et al. High-dose interferon-γ promotes abortion in mice by suppressing Treg and Th17 polarization. J. Interferon Cytokine Res 34, 394–403 (2014). [Europe PMC free article] [Abstract] [Google Scholar]
86. Sun Q-H, Peng J-P, Xia H-F & Yang Y IFN-γ promotes apoptosis of the uterus and placenta in pregnant rat and human cytotrophoblast cells. J. Interferon Cytokine Res 27, 567–578 (2007). [Abstract] [Google Scholar]
87. El Costa H et al. Effector functions of human decidual NK cells in healthy early pregnancy are dependent on the specific engagement of natural cytotoxicity receptors. J. Reprod. Immunol 82, 142–147 (2009). [Abstract] [Google Scholar]
88. Koopman LA et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J. Exp. Med 198, 1201–1212 (2003). [Europe PMC free article] [Abstract] [Google Scholar]
89. Hiby SE et al. Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2. J. Clin. Invest 120, 4102–4110 (2010). [Europe PMC free article] [Abstract] [Google Scholar]
90. Peraçoli JC, Fortes MR, Rudge MV, Rezkallah-Iwasso MT & Peraçoli MT Studies of natural killer cells in pregnancy-induced hypertension. Braz. J. Med. Biol. Res 28, 655–661 (1995). [Abstract] [Google Scholar]
91. Borzychowski AM, Croy BA, Chan WL, Redman CW & Sargent IL Changes in systemic type 1 and type 2 immunity in normal pregnancy and pre-eclampsia may be mediated by natural killer cells. Eur. J. Immunol 35, 3054–3063 (2005). [Abstract] [Google Scholar]
92. Zhang Z et al. Studies on activity of NK cells in preeclampsia patients. J. Huazhong Univ. Sci. Technol. Med. Sci 24, 473–475 (2004). [Abstract] [Google Scholar]
93. Bachmayer N, Rafik Hamad R, Liszka L, Bremme K & Sverremark-Ekström E Aberrant uterine natural killer (NK)-cell expression and altered placental and serum levels of the NK-cell promoting cytokine interleukin-12 in pre-eclampsia. Am. J. Reprod. Immunol 56, 292–301 (2006). [Abstract] [Google Scholar]
94. Travis OK et al. Interleukin-17 signaling mediates cytolytic natural killer cell activation in response to placental ischemia. Am. J. Physiol. Regul. Integr. Comp. Physiol 318, R1036–R1046 (2020). [Europe PMC free article] [Abstract] [Google Scholar]
95. Travis OK et al. Adoptive transfer of placental ischemia-stimulated natural killer cells causes a preeclampsia-like phenotype in pregnant rats. Am. J. Reprod. Immunol 85, e13386 (2021). [Europe PMC free article] [Abstract] [Google Scholar]
96. Richani K et al. Normal pregnancy is characterized by systemic activation of the complement system. J. Matern. Fetal Neonatal Med 17, 239–245 (2005). [Europe PMC free article] [Abstract] [Google Scholar]
97. Derzsy Z, Prohászka Z, Rigó J, Füst G & Molvarec A Activation of the complement system in normal pregnancy and preeclampsia. Mol. Immunol 47, 1500–1506 (2010). [Abstract] [Google Scholar]
98. Reis ES, Mastellos DC, Hajishengallis G & Lambris JD New insights into the immune functions of complement. Nat. Rev. Immunol 19, 503–516 (2019). [Europe PMC free article] [Abstract] [Google Scholar]
99. Lynch AM et al. Alternative complement pathway activation fragment Bb in early pregnancy as a predictor of preeclampsia. Am. J. Obstet. Gynecol 198, 385.e1–385.e9 (2008). [Europe PMC free article] [Abstract] [Google Scholar]
100. Lynch AM et al. Prepregnancy obesity and complement system activation in early pregnancy and the subsequent development of preeclampsia. Am. J. Obstet. Gynecol 206, 428.e1–428.e8 (2012). [Europe PMC free article] [Abstract] [Google Scholar]
101. Lillegard KE et al. Complement activation is critical for placental ischemia-induced hypertension in the rat. Mol. Immunol 56, 91–97 (2013). [Europe PMC free article] [Abstract] [Google Scholar]
102. Burwick RM et al. Terminal complement activation in preeclampsia. Obstet. Gynecol 132, 1477–1485 (2018). [Abstract] [Google Scholar]
103. Rampersad R, Barton A, Sadovsky Y & Nelson DM The C5b-9 membrane attack complex of complement activation localizes to villous trophoblast injury in vivo and modulates human trophoblast function in vitro. Placenta 29, 855–861 (2008). [Europe PMC free article] [Abstract] [Google Scholar]
104. Holers VM et al. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J. Exp. Med 195, 211–220 (2002). [Europe PMC free article] [Abstract] [Google Scholar]
105. Denny KJ et al. Elevated complement factor C5a in maternal and umbilical cord plasma in preeclampsia. J. Reprod. Immunol 97, 211–216 (2013). [Abstract] [Google Scholar]
106. Guseh SH et al. Urinary excretion of C5b-9 is associated with the anti-angiogenic state in severe preeclampsia. Am. J. Reprod. Immunol 73, 437–444 (2015). [Abstract] [Google Scholar]
107. He Y et al. Expression of the complement system’s activation factors in plasma of patients with early/late-onset severe pre-eclampsia. Am. J. Reprod. Immunol 76, 205–211 (2016). [Abstract] [Google Scholar]
108. He YD et al. Dysregulation of complement system during pregnancy in patients with preeclampsia: a prospective study. Mol. Immunol 122, 69–79 (2020). [Abstract] [Google Scholar]
109. Larsen JB et al. Lectin pathway proteins of the complement system in normotensive pregnancy and pre-eclampsia. Am. J. Reprod. Immunol 81, e13092 (2019). [Abstract] [Google Scholar]
110. Wu W et al. Polymorphisms in complement genes and risk of preeclampsia in Taiyuan, China. Inflamm. Res 65, 837–845 (2016). [Abstract] [Google Scholar]
111. Lokki AI et al. Analysis of complement. Front. Immunol 8, 589 (2017). [Europe PMC free article] [Abstract] [Google Scholar]
112. Salmon JE et al. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med. 8, e1001013 (2011). [Europe PMC free article] [Abstract] [Google Scholar]
113. Fang CJ et al. Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood 111, 624–632 (2008). [Europe PMC free article] [Abstract] [Google Scholar]
114. Klonoff-Cohen HS, Savitz DA, Cefalo RC & McCann MF An epidemiologic study of contraception and preeclampsia. JAMA 262, 3143–3147 (1989). [Abstract] [Google Scholar]
115. Robertson SA, Care AS & Moldenhauer LM Regulatory T cells in embryo implantation and the immune response to pregnancy. J. Clin. Invest 128, 4224–4235 (2018). [Europe PMC free article] [Abstract] [Google Scholar]
116. Masoudian P et al. Oocyte donation pregnancies and the risk of preeclampsia or gestational hypertension: a systematic review and metaanalysis. Am. J. Obstet. Gynecol 214, 328–339 (2016). [Abstract] [Google Scholar]
117. Laresgoiti-Servitje E A leading role for the immune system in the pathophysiology of preeclampsia. J. Leukoc. Biol 94, 247–257 (2013). [Abstract] [Google Scholar]
118. Darmochwal-Kolarz D et al. The predominance of Th17 lymphocytes and decreased number and function of Treg cells in preeclampsia. J. Reprod. Immunol 93, 75–81 (2012). [Abstract] [Google Scholar]
119. Kondelkova K et al. Regulatory T cells (TREG) and their roles in immune system with respect to immunopathological disorders. Acta Med. 53, 73–77 (2010). [Abstract] [Google Scholar]
120. Hosseini A, Dolati S, Hashemi V, Abdollahpour-Alitappeh M & Yousefi M Regulatory T and T helper 17 cells: their roles in preeclampsia. J. Cell. Physiol 233, 6561–6573 (2018). [Abstract] [Google Scholar]
121. Harmon AC et al. The role of inflammation in the pathology of preeclampsia. Clin. Sci 130, 409–419 (2016). [Europe PMC free article] [Abstract] [Google Scholar]
122. Jørgensen N, Persson G & Hviid TVF The tolerogenic function of regulatory T cells in pregnancy and cancer. Front. Immunol 10, 911 (2019). [Europe PMC free article] [Abstract] [Google Scholar]
123. Lucca LE & Dominguez-Villar M Modulation of regulatory T cell function and stability by co-inhibitory receptors. Nat. Rev. Immunol 20, 680–693 (2020). [Abstract] [Google Scholar]
124. Tilburgs T et al. Fetal-maternal HLA-C mismatch is associated with decidual T cell activation and induction of functional T regulatory cells. J. Reprod. Immunol 82, 148–157 (2009). [Abstract] [Google Scholar]
125. Saito S, Shiozaki A, Nakashima A, Sakai M & Sasaki Y The role of the immune system in preeclampsia. Mol. Asp. Med 28, 192–209 (2007). [Abstract] [Google Scholar]
126. Robertson SA et al. Therapeutic potential of regulatory T cells in preeclampsia — opportunities and challenges. Front. Immunol 10, 478 (2019). [Europe PMC free article] [Abstract] [Google Scholar]
127. Santner-Nanan B et al. Systemic increase in the ratio between Foxp3+ and IL-17-producing CD4+ T cells in healthy pregnancy but not in preeclampsia. J. Immunol 183, 7023–7030 (2009). [Abstract] [Google Scholar]
128. Sasaki Y et al. Proportion of peripheral blood and decidual CD4+ CD25bright regulatory T cells in pre-eclampsia. Clin. Exp. Immunol 149, 139–145 (2007). [Abstract] [Google Scholar]
129. Tsuda S, Nakashima A, Shima T & Saito S New paradigm in the role of regulatory T cells during pregnancy. Front. Immunol 10, 573 (2019). [Europe PMC free article] [Abstract] [Google Scholar]
130. Novotny SR et al. Activating autoantibodies to the angiotensin II type I receptor play an important role in mediating hypertension in response to adoptive transfer of CD4+ T lymphocytes from placental ischemic rats. Am. J. Physiol. Regul. Integr. Comp. Physiol 302, R1197–R1201 (2012). [Europe PMC free article] [Abstract] [Google Scholar]
131. Harmon AC et al. Placental CD4+ T cells isolated from preeclamptic women cause preeclampsia-like symptoms in pregnant nude-athymic rats. Pregnancy Hypertens. 15, 7–11 (2019). [Europe PMC free article] [Abstract] [Google Scholar]
132. Cornelius DC et al. An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia. Am. J. Physiol. Regul. Integr. Comp. Physiol 309, R884–R891 (2015). [Europe PMC free article] [Abstract] [Google Scholar]
133. Care AS et al. Reduction in regulatory T cells in early pregnancy causes uterine artery dysfunction in mice. Hypertension 72, 177–187 (2018). [Abstract] [Google Scholar]
134. Deer E et al. CD4+ T cells cause renal and placental mitochondrial oxidative stress as mechanisms of hypertension in response to placental ischemia. Am. J. Physiol. Renal Physiol 320, F47–F54 (2021). [Europe PMC free article] [Abstract] [Google Scholar]
135. Novotny S et al. CD4+ T cells play a critical role in mediating hypertension in response to placental ischemia. J. Hypertens. Open Access 2, 14873 (2013). [Europe PMC free article] [Abstract] [Google Scholar]
136. Reeve K et al. Placental CD4+ T cells from preeclamptic patients cause autoantibodies to the angiotensin II type I receptor and hypertension in a pregnant rat model of preeclampsia. Exploration Med. 3, 99–111 (2022). [Europe PMC free article] [Abstract] [Google Scholar]
137. Deer E et al. Progesterone induced blocking factor reduces hypertension and placental mitochondrial dysfunction in response to sFlt-1 during pregnancy. Cells 10, 2817 (2021). [Europe PMC free article] [Abstract] [Google Scholar]
138. Singh RP et al. Th17 cells in inflammation and autoimmunity. Autoimmun. Rev 13, 1174–1181 (2014). [Abstract] [Google Scholar]
139. Kamali AN et al. A role for Th1-like Th17 cells in the pathogenesis of inflammatory and autoimmune disorders. Mol. Immunol 105, 107–115 (2019). [Abstract] [Google Scholar]
140. Fu B et al. Natural killer cells promote immune tolerance by regulating inflammatory TH17 cells at the human maternal–fetal interface. Proc. Natl Acad. Sci 110, E231–E240 (2013). [Europe PMC free article] [Abstract] [Google Scholar]
141. Fu B, Tian Z & Wei H TH17 cells in human recurrent pregnancy loss and pre-eclampsia. Cell. Mol. Immunol 11, 564–570 (2014). [Europe PMC free article] [Abstract] [Google Scholar]
142. Cornelius DC et al. Reduced uterine perfusion pressure T-helper 17 cells cause pathophysiology associated with preeclampsia during pregnancy. Am. J. Physiol. Regul. Integr. Comp. Physiol 311, R1192–R1199 (2016). [Europe PMC free article] [Abstract] [Google Scholar]
143. Nguyen H et al. Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension. Cardiovascular Res. 97, 696–704 (2013). [Europe PMC free article] [Abstract] [Google Scholar]
144. Gaffen SL An overview of IL-17 function and signaling. Cytokine 43, 402–407 (2008). [Europe PMC free article] [Abstract] [Google Scholar]
145. Dinh QN, Drummond GR, Sobey CG & Chrissobolis S Roles of inflammation, oxidative stress, and vascular dysfunction in hypertension. Biomed. Res. Int 2014, 406960 (2014). [Europe PMC free article] [Abstract] [Google Scholar]
146. Cornelius DC et al. Administration of interleukin-17 soluble receptor C suppresses TH17 cells, oxidative stress, and hypertension in response to placental ischemia during pregnancy. Hypertension 62, 1068–1073 (2013). [Europe PMC free article] [Abstract] [Google Scholar]
147. Zhou L et al. TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature 453, 236–240 (2008). [Europe PMC free article] [Abstract] [Google Scholar]
148. Kawahara T, Ohdan H, Zhao G, Yang YG & Sykes M Peritoneal cavity B cells are precursors of splenic IgM natural antibody-producing cells. J. Immunol 171, 5406–5414 (2003). [Abstract] [Google Scholar]
149. Allman D, Wilmore JR & Gaudette BT The continuing story of T-cell independent antibodies. Immunol. Rev 288, 128–135 (2019). [Europe PMC free article] [Abstract] [Google Scholar]
150. Muzzio D, Zenclussen AC & Jensen F The role of B cells in pregnancy: the good and the bad. Am. J. Reprod. Immunol 69, 408–412 (2013). [Abstract] [Google Scholar]
151. Jensen F et al. CD19+CD5+ cells as indicators of preeclampsia. Hypertension 59, 861–868 (2012). [Abstract] [Google Scholar]
152. Wallukat G et al. Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J. Clin. Invest 103, 945–952 (1999). [Europe PMC free article] [Abstract] [Google Scholar]
153. Torricelli M et al. Levels of antibodies against protein C and protein S in pregnancy and in preeclampsia. J. Matern. Fetal Neonatal Med 22, 993–999 (2009). [Abstract] [Google Scholar]
154. Nor Azlin MI et al. Thyroid autoantibodies and associated complications during pregnancy. J. Obstet. Gynaecol 30, 675–678 (2010). [Abstract] [Google Scholar]
155. Hubel CA et al. Agonistic angiotensin II type 1 receptor autoantibodies in postpartum women with a history of preeclampsia. Hypertension 49, 612–617 (2007). [Abstract] [Google Scholar]
156. Rieber-Mohn AB et al. Auto-antibodies against the angiotensin II type I receptor in women with uteroplacental acute atherosis and preeclampsia at delivery and several years postpartum. J. Reprod. Immunol 128, 23–29 (2018). [Abstract] [Google Scholar]
157. Zeng B, Kwak-Kim J, Liu Y & Liao AH Treg cells are negatively correlated with increased memory B cells in pre-eclampsia while maintaining suppressive function on autologous B-cell proliferation. Am. J. Reprod. Immunol 70, 454–463 (2013). [Abstract] [Google Scholar]
158. Cornelius DC et al. Blockade of CD40 ligand for intercellular communication reduces hypertension, placental oxidative stress, and AT1-AA in response to adoptive transfer of CD4+ T lymphocytes from RUPP rats. Am. J. Physiol. Regul. Integr. Comp. Physiol 309, R1243–R1250 (2015). [Europe PMC free article] [Abstract] [Google Scholar]
159. Robillard P-Y, Dekker G, Scioscia M & Saito S Progress in the understanding of the pathophysiology of immunologic maladaptation related to early-onset preeclampsia and metabolic syndrome related to late-onset preeclampsia. Am. J. Obstet. Gynecol 226, S867–S875 (2022). [Abstract] [Google Scholar]
160. Robillard P-Y Epidemiological evidence that severe obese women (pre-pregnancy BMI≥ 40 kg/m2) should lose weight during their pregnancy. J. Matern. Fetal Neonatal Med 35, 6618–6623 (2021). [Abstract] [Google Scholar]
161. Dechend R et al. AT1 receptor agonistic antibodies from preeclamptic patients cause vascular cells to express tissue factor. Circulation 101, 2382–2387 (2000). [Abstract] [Google Scholar]
162. Regal JF et al. Role of IgM and angiotensin II type I receptor autoantibodies in local complement activation in placental ischemia-induced hypertension in the rat. Mol. Immunol 78, 38–47 (2016). [Europe PMC free article] [Abstract] [Google Scholar]
163. Murphy SR & Cockrell K Regulation of soluble fms-like tyrosine kinase-1 production in response to placental ischemia/hypoxia: role of angiotensin II. Physiol. Rep 3, 10.14814/phy2.12310 (2015). [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
164. Quan A Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists. Early Hum. Dev 82, 23–28 (2006). [Abstract] [Google Scholar]
165. Elliott SE et al. Characterization of antibody specificities associated with preeclampsia. Hypertension 63, 1086–1093 (2014). [Europe PMC free article] [Abstract] [Google Scholar]
166. Wenzel K et al. Angiotensin II type 1 receptor antibodies and increased angiotensin II sensitivity in pregnant rats. Hypertension 58, 77–84 (2011). [Europe PMC free article] [Abstract] [Google Scholar]
167. Irani RA et al. The detrimental role of angiotensin receptor agonistic autoantibodies in intrauterine growth restriction seen in preeclampsia. J. Exp. Med 206, 2809–2822 (2009). [Europe PMC free article] [Abstract] [Google Scholar]
168. Xia Y, Wen H, Bobst S, Day MC & Kellems RE Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human trophoblast cells. J. Soc. Gynecol. Investig 10, 82–93 (2003). [Abstract] [Google Scholar]
169. Thway TM et al. Antibodies from preeclamptic patients stimulate increased intracellular Ca2+ mobilization through angiotensin receptor activation. Circulation 110, 1612–1619 (2004). [Abstract] [Google Scholar]
170. Brewer J et al. Endothelin-1, oxidative stress, and endogenous angiotensin II: mechanisms of angiotensin II type I receptor autoantibody-enhanced renal and blood pressure response during pregnancy. Hypertension 62, 886–892 (2013). [Europe PMC free article] [Abstract] [Google Scholar]
171. Cunningham MW et al. AT1-AA (Angiotensin II Type 1 receptor agonistic autoantibody) blockade prevents preeclamptic symptoms in placental ischemic rats. Hypertension 71, 886–893 (2018). [Europe PMC free article] [Abstract] [Google Scholar]
172. Vaka VR et al. Blockade of endogenous angiotensin II type I receptor agonistic autoantibody activity improves mitochondrial reactive oxygen species and hypertension in a rat model of preeclampsia. Am. J. Physiol. Regul. Integr. Comp. Physiol 318, R256–R262 (2020). [Europe PMC free article] [Abstract] [Google Scholar]
173. Duncan JW et al. Angiotensin II type 1 receptor autoantibody blockade improves cerebral blood flow autoregulation and hypertension in a preclinical model of preeclampsia. Hypertens. Pregnancy 39, 451–460 (2020). [Abstract] [Google Scholar]
174. Panayi GS B cells: a fundamental role in the pathogenesis of rheumatoid arthritis? Rheumatology 44, ii3–ii7 (2005). [Abstract] [Google Scholar]
175. Cianchini G et al. Treatment of severe pemphigus with rituximab: report of 12 cases and a review of the literature. Arch. Dermatol 143, 1033–1038 (2007). [Abstract] [Google Scholar]
176. Cianchini G et al. Severe persistent pemphigoid gestationis: long-term remission with rituximab. Br. J. Dermatol 157, 388–389 (2007). [Abstract] [Google Scholar]
177. LaMarca B et al. Hypertension in response to placental ischemia during pregnancy: role of B lymphocytes. Hypertension 57, 865–871 (2011). [Europe PMC free article] [Abstract] [Google Scholar]
178. Chakravarty EF, Murray ER, Kelman A & Farmer P Pregnancy outcomes after maternal exposure to rituximab. Blood 117, 1499–1506 (2011). [Abstract] [Google Scholar]
179. Das G et al. Rituximab before and during pregnancy: a systematic review, and a case series in MS and NMOSD. Neurol. Neuroimmunol. Neuroinflamm 5, e453 (2018). [Europe PMC free article] [Abstract] [Google Scholar]
180. Smith JB et al. Rituximab, MS, and pregnancy. Neurol. Neuroimmunol. Neuroinflamm 7, 10.1212/NXI.0000000000000734 (2020). [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
181. Friedrichs B et al. The effects of rituximab treatment during pregnancy on a neonate. Haematologica 91, 1426–1427 (2006). [Abstract] [Google Scholar]
182. Vaught AJ et al. Direct evidence of complement activation in HELLP syndrome: a link to atypical hemolytic uremic syndrome. Exp. Hematol 44, 390–398 (2016). [Europe PMC free article] [Abstract] [Google Scholar]
183. Burwick RM, Fichorova RN, Dawood HY, Yamamoto HS & Feinberg BB Urinary excretion of C5b-9 in severe preeclampsia: tipping the balance of complement activation in pregnancy. Hypertension 62, 1040–1045 (2013). [Abstract] [Google Scholar]
184. Stefanovic V The extended use of eculizumab in pregnancy and complement activation-associated diseases affecting maternal, fetal and neonatal kidneys — the future is now? J. Clin. Med 8, 407 (2019). [Europe PMC free article] [Abstract] [Google Scholar]
185. Lokki AI, Haapio M & Heikkinen-Eloranta J Eculizumab treatment for postpartum HELLP syndrome and aHUS — case report. Front. Immunol 11, 548 (2020). [Europe PMC free article] [Abstract] [Google Scholar]
186. Smith DD & Costantine MM The role of statins in the prevention of preeclampsia. Am. J. Obstet. Gynecol 226, S1171–S1181 (2020). [Europe PMC free article] [Abstract] [Google Scholar]
187. Lefkou E et al. Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy. J. Clin. Investig 126, 2933–2940 (2016). [Europe PMC free article] [Abstract] [Google Scholar]
188. Rolnik DL et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N. Engl. J. Med 377, 613–622 (2017). [Abstract] [Google Scholar]
189. Dodd JM, Jones L, Flenady V, Cincotta R & Crowther CA Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth. Cochrane Database Syst. Rev (2013). [Europe PMC free article] [Abstract] [Google Scholar]
190. Amaral LM et al. 17-Hydroxyprogesterone caproate improves hypertension and renal endothelin-1 in response to sFlt-1 induced hypertension in pregnant rats. Pregnancy Hypertens. 22, 151–155 (2020). [Europe PMC free article] [Abstract] [Google Scholar]
191. Singh J, Ahmed A & Girardi G Role of complement component C1q in the onset of preeclampsia in mice. Hypertension 58, 716–724 (2011). [Abstract] [Google Scholar]
192. Shah DM Role of the renin-angiotensin system in the pathogenesis of preeclampsia. Am. J. Physiol. Renal Physiol 288, F614–F625 (2005). [Abstract] [Google Scholar]
193. Xia Y, Ramin SM & Kellems RE Potential roles of angiotensin receptor-activating autoantibody in the pathophysiology of preeclampsia. Hypertension 50, 269–275 (2007). [Europe PMC free article] [Abstract] [Google Scholar]
194. Cunningham MW et al. Agonistic autoantibodies to the angiotensin II type 1 receptor enhance angiotensin II-induced renal vascular sensitivity and reduce renal function during pregnancy. Hypertension 68, 1308–1313 (2016). [Europe PMC free article] [Abstract] [Google Scholar]
195. Zhang W et al. Mechanism of agonistic angiotensin II type I receptor autoantibody-amplified contractile response to Ang II in the isolated rat thoracic aorta. Acta Biochim. Biophys. Sin 47, 851–856 (2015). [Abstract] [Google Scholar]
196. Singh KD et al. Novel allosteric ligands of the angiotensin receptor AT1R as autoantibody blockers. Proc. Natl Acad. Sci. USA 118, 10.1073/pnas.2019126118 (2021). [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
197. LaMarca B et al. Hypertension in response to autoantibodies to the angiotensin II type I receptor (AT1-AA) in pregnant rats: role of endothelin-1. Hypertension 54, 905–909 (2009). [Europe PMC free article] [Abstract] [Google Scholar]
198. Parrish MR et al. Hypertension in response to AT1-AA: role of reactive oxygen species in pregnancy-induced hypertension. Am. J. Hypertens 24, 835–840 (2011). [Abstract] [Google Scholar]
199. Zhou CC et al. Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice. Nat. Med 14, 855–862 (2008). [Europe PMC free article] [Abstract] [Google Scholar]
200. Parrish MR et al. The effect of immune factors, tumor necrosis factor-α, and agonistic autoantibodies to the angiotensin II type I receptor on soluble fms-like tyrosine-1 and soluble endoglin production in response to hypertension during pregnancy. Am. J. Hypertens 23, 911–916 (2010). [Europe PMC free article] [Abstract] [Google Scholar]
201. Zhou CC et al. Angiotensin II induces soluble fms-like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy. Circ. Res 100, 88–95 (2007). [Europe PMC free article] [Abstract] [Google Scholar]
202. Zhou CC Upregulation of placental soluble fms-like tyrosine kinase 1 by AT1 receptor agonistic autoantibodies in preeclampsia. Hypertens. Pregnancy 25, 38 (2006). [Google Scholar]
203. Zhou CC et al. Angiotensin receptor agonistic autoantibody-mediated tumor necrosis factor-α induction contributes to increased soluble endoglin production in preeclampsia. Circulation 121, 436–444 (2010). [Europe PMC free article] [Abstract] [Google Scholar]
204. Cunningham MW et al. Renal natural killer cell activation and mitochondrial oxidative stress; new mechanisms in AT1-AA mediated hypertensive pregnancy. Pregnancy Hypertens. 15, 72–77 (2019). [Europe PMC free article] [Abstract] [Google Scholar]
205. Wang ZC et al. Valsartan reduces AT1-AA-induced apoptosis through suppression oxidative stress mediated ER stress in endothelial progenitor cells. Eur. Rev. Med. Pharmacol. Sci 21, 1159–1168 (2017). [Abstract] [Google Scholar]
206. Dechend R et al. AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase. Circulation 107, 1632–1639 (2003). [Abstract] [Google Scholar]
207. Vaka VR et al. Role of mitochondrial dysfunction and reactive oxygen species in mediating hypertension in the reduced uterine perfusion pressure rat model of preeclampsia. Hypertension 72, 703–711 (2018). [Europe PMC free article] [Abstract] [Google Scholar]
208. Parrish MR et al. Angiotensin II type 1 autoantibody induced hypertension during pregnancy is associated with renal endothelial dysfunction. Gend. Med 8, 184–188 (2011). [Europe PMC free article] [Abstract] [Google Scholar]

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